Prostate Cancer (PC) is a major health risk for men in the US. A major difficulty in the diagnosis of PC is that unlike many other cancers, PC cannot be accurately diagnosed by radiology. As a result, the urologists usually perform a standardized 12-core biopsy which samples the prostate in a systematic but blind fashion, resulting in two major issues negatively impacting the management of a large number of men. One issue is that the biopsy can miss a significant portion of PC. Because a negative biopsy does not rule out the presence of PC, men with increased PSA but negative biopsies are subject to close followup including repeat biopsies although the majority of the men have benign conditions only. A different but equally important issue is that > 80% of PCs identified through PSA screening are indolent and do not need treatment. Because the biopsy is performed in a blind but not targeted fashion, it is difficult to predict the biologic behavior of the PC, resulting in overtreatment of large number of men with only indolent tumors. This proposal attempts to address these clinical issues through the identification of biomarkers in biopsy tissue. We hypothesize that there are specific gene expression changes in PC-adjacent, histologically benign prostate, and such changes are likely cell-type specific. We have developed technologies to obtain pure sub-populations of epithelial cell from fresh human prostate tissue and identified a number of cell-type specific markers differentially expressed in basal and luminal cells from histologically benign prostate adjacent to PC vs normal prostate from men without PC. These genes may serve as biomarkers to predict the presence or absence of PC in men with increased PSA but negative biopsies. The study will be extended to develop cell type-specific biomarkers that predict the aggressiveness of the PC in men with positive biopsies. The proposal has two specific aims: Aim 1. Developing biomarkers to predict the presence or absence of PC in men with increased PSA but negative biopsies: We will take the candidate biomarkers from the microarray study and optimize immunohistochemistry (IHC) conditions for the detection of the corresponding proteins in prostate tissue. The biomarkers will be tested in benign prostate biopsy tissue from patients known to harbor PC or be free of PC to determine their clinical utility Aim 2. Developing biomarkers that predict the aggressiveness of PC: We will repeat the microarray experiment using prostate tissue adjacent to aggressive PC and indolent PC respectively to compare their differences in gene expression, which will reveal potential biomarkers that may predict the aggressiveness of the adjacent PC. IHC tests will be developed for the top candidates to determine which ones may be developed into clinically useful tests.